EOGT Enables Residual Notch Signaling in Mouse Intestinal Cells Lacking POFUT1

Abstract

AbstractNotch signaling determines cell fates in mouse intestine. Notch receptors contain multiple epidermal growth factor-like (EGF) repeats modified by O-glycans that regulate Notch signaling. Conditional deletion of protein O-fucosyltransferase 1 (Pofut1) substantially reduces Notch signaling and markedly perturbs lineage development in mouse intestine. However, mice with inactivatedPofut1are viable, whereas complete elimination of Notch signaling in intestine is lethal. Here we investigate whether residual Notch signaling enabled by EOGT permits mice lackingPofut1in intestine to survive. Mice globally lackingEogtalone were grossly unaffected in intestinal development. In contrast, mice lacking bothEogtandPofut1died at ∼28 days after birth with greater loss of body weight, a greater increase in the numbers of goblet and Paneth cells, and greater downregulation of Notch target genes, compared toPofut1deletion alone. These data establish that both O-fucose and O-GlcNAc glycans are fundamental to Notch signaling in the intestine and provide new insights into roles for O-glycans in regulating Notch ligand binding. Finally, EOGT and O-GlcNAc glycans provide residual Notch signaling and support viability in mice lackingPofut1in the intestine.